The present invention relates to new substituted (dihydro)benzoxazine and (dihydro) benzothiazine compounds that exhibit very valuable pharmacological properties in relation to melatoninergic receptors.
1. Description of the Prior Art
There may be found in the literature numerous substituted benzoxazine and benzothiazine structures for use both in synthesis (Tetrahedron, 53 (26), 1997, pp. 8853-8870; Heterocycl. Commun., 2 (3), 1996, pp. 273-274; J. Chem. Soc., Perkin Trans. 1, (10), 1991, pp. 2525-2529; Chem. Pharm. Bull., 34 (1), 1986, pp. 130-139; Indian J. Pharm., 35 (2), 1973, pp. 58-59) and as modulators of potassium channels (Eur J. Med. Chem., 33 (12), 1998, pp. 957-967; Chem. Pharm. Bull., 44 (1), 1996, pp. 103-114), or also as anti-cancer agents (Heterocycl. Commun., 3 (3), 1997, pp. 279-284; Heterocycl. Commun., 2 (6), 1996, pp. 587-592; Anti-Cancer Drugs, 6 (5), 1995, pp. 693-696).
2. Background of the Invention
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. Its half-life is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possiblity of providing the clinician with melatonin analogues that are metabolically more stable and have an agonist or antagonist character and that may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage to have specific ligands available. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they show very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic binding sites.
The present invention relates more especially to the compounds of formula (I): 
wherein:
R1 represents a halogen atom or a group R, OR, SR, SO2NRRxe2x80x2, xe2x80x94NRRxe2x80x2, 
(wherein Z represent a sulpur atom or an oxygen atom and R, Rxe2x80x2 and Rxe2x80x3, which are identical or different, represent a hydrogen atom or an unsubstituted or substituted, linear or branched (C1-C6)alkyl group, an unsubstituted or substituted, linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted, linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)-cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which alkyl is linear or branched, an aryl group, an aryl(C1-C6)alkyl group in which alkyl is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which alkyl is linear or branched,
and wherein (R and Rxe2x80x2) or (Rxe2x80x2 and Rxe2x80x3) may together form, with the nitrogen atom carrying them, a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group),
G represents an alkylene chain containing from 2 to 4 carbon atoms when A represents a group 
and from 1 to 4 carbon atoms in all other cases, G being optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore),
A represents a group 
(wherein R, Rxe2x80x2 Rxe2x80x3 and Z are as defined hereinbefore),
R2 represents a halogen atom or a group R, OR, COR, COOR or OCOR (wherein R is as defined hereinbefore),
X represents an oxygen atom or a sulphur atom,
the symbol  denotes that the bond is single or double, the valency of the atoms being respected,
wherein:
the term xe2x80x9csubstitutedxe2x80x9d applied to xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d denotes that those groups may be substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, polyhaloalkyl, amino (unsubstituted or substituted by one or two linear or branched (C1-C6)alkyl groups) and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to xe2x80x9ccycloalkylalkylxe2x80x9d denotes that the cyclic moiety of the group is substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, polyhaloalkyl, amino (unsubstituted or substituted by one or two linear or branched (C1-C6)alkyl groups) and halogen atoms,
xe2x80x9carylxe2x80x9d denotes a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d denotes any mono- or bi-cyclic aromatic group containing from one to three hetero atoms selected from oxygen, sulphur and nitrogen, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido and halogen atoms,
to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric, oxalic acid, etc.
Amongs the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom.
The invention relates more especially to the benzoxazine compounds, and more preferably to the dihydrobenzoxazine compounds.
Preferred substituents R1 are the groups alkyl, alkoxy and hydroxy.
Preferred substituents R2 are the hydrogen atom and the groups aryl, heteroaryl, arylalkyl and heteroarylalkyl, and more especially the unsubstituted or substituted phenyl group.
Advantageously, the invention relates to the compounds of formula (I) wherein G represents a (CH2)n chain in which n is 2 or 3.
Preferred substituents A are the groups NHCOR and CONHR.
The invention relates even more especially to the following compounds of formula (I):
N-[2-(6-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]acetamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]acetamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]butanamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-butenamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclopropanecarboxamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]benzamide,
N[2-(6-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide,
N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]acetamide,
N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]benzamide,
N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide,
N-[2-(6-methoxy-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]butanamide,
N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]acetamide,
N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-furamide,
N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]benzamide,
N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]butanamide,
N-[2-(6-methoxy-2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclopropanecarboxamide.
The enantiomers, diastereoisomers and also the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The invention extends also to a process for the preparation of the compounds of formula (I) which is characterised in that there is used as starting material a compound of formula (II): 
wherein R1, R2, X and the symbol  are as defined in formula (I),
with which there is reacted, in basic medium, a compound of formula (III)
Brxe2x80x94Gxe2x80x94CNxe2x80x83xe2x80x83(III) 
wherein G is as defined in formula (I),
to yield a compound of formula (IV): 
wherein R1, R2, X, G and the symbol  are as defined hereinbefore,
which is subjected to hydrolysis, under acid or basic conditions, to yield a compound of formula (V): 
wherein R1, R2, X, G and the symbol  have the same definitions as hereinbefore, which is acted upon, in the presence of a coupling agent or after conversion into the corresponding acid chloride, by an amine HNRRxe2x80x2 wherein R and Rxe2x80x2 are as defined in formula (I), to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1, R2, X, G, R, Rxe2x80x2 and the symbol  are as defined hereinbefore,
which compound of formula (I/a) is subjected, when R and Rxe2x80x2 simultaneously represent a hydrogen atom, to the action of NaOBr to yield, after hydrolysis, a compound of formula (VI): 
wherein R1, R2, X, G and the symbol  are as defined hereinbefore,
which compounds of formula (VI) (which furthermore can be obtained by reduction of the compound of formula (IV)) are subjected to the action:
of an acyl chloride of formula (VII): 
wherein R is as defined hereinbefore, or to a corresponding (mixed or symmetrical) acid anhydride,
to obtain a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein R1, R2, R, X, G and the symbol  have the same definitions as hereinbefore,
or of a compound of formula (VIII):
Oxe2x95x90Cxe2x95x90Nxe2x80x94Rxe2x80x83xe2x80x83(VIII) 
wherein R is as defined hereinbefore,
to yield a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R1, R2, R, X, G and the symbol  are as defined hereinbefore,
wherein the compounds of formulae (I/b) and (I/c) may be subjected to the action of a compound of formula (IX):
Raxe2x80x94Jxe2x80x83xe2x80x83(IX) 
wherein Ra may have any of the meanings of R with the exception of a hydrogen atom and J represents a leaving group, such as a halogen atom or a tosyl group,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein R1, R2, X, G, Ra and the symbol  have the same definitions as hereinbefore and W represents a group R or xe2x80x94NRRxe2x80x2 wherein R and Rxe2x80x2 are as defined hereinbefore,
and/or the compounds of formulae (I/a), (I/b), (I/c) and (I/d) may be subjected to the action of a thionisation agent, such as Lawesson""s reagent, to yield a compound of formula (I/e), a particular case of the compounds of formula (I): 
wherein R1, R2, X, G and the symbol  are as defined hereinbefore and Y represents a group 
wherein R, Rxe2x80x2 and W are as defined hereinbefore,
the compounds (I/a) to (I/e) constituting the totality of the compounds of formula (I) and wherein those compounds may be purified according to a conventional separation technique, may be converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and may optionally be separated into their isomers according to a conventional separation technique.
The compounds of formula (II) are either commercially available, or accessible to the person skilled in the art by conventional chemical reactions.
In particular, the compounds of formula (II) can be obtained starting from compounds of formula (X): 
wherein R1 and X are as defined hereinbefore,
which are subjected to catalytic hydrogenation to obtain a compound of formula (XI): 
wherein R1 and X are as defined hereinbefore,
which is acetylated to yield a compound of formula (XII): 
wherein R1 and X are as defined hereinbefore,
which is acted upon by a compound of formula (XIII): 
wherein Hal represents a halogen atom and R2 is as defined hereinbefore,
to yield a compound of formula (XIV): 
wherein R1 , R2 and X are as defined hereinbefore,
which is hydrolysed in basic medium to obtain a compound of formula (XV), a particular case of the compounds of formula (II): 
wherein R1, R2 and X are as defined hereinbefore,
it being equally possible for a compound of formula (XV) to be obtained starting from a compound of formula (X), which is subjected to the action of a compound of formula (XVI): 
wherein Hal represents a halogen atom and R2 is as defined hereinbefore,
to yield a compound of formula (XVII): 
wherein R1, X and R2 are as defined hereinbefore,
which is subjected to catalytic hydrogenation to yield a compound of formula (XV), a particular case of the compounds of formula (II),
it being possible, moreover, for a compound of formula (XV) in which the group R2 is in the ortho position to X to be obtained starting from a compound of formula (XI), which is subjected to the action of a compound of formula (XVIII): 
wherein R2 is as defined hereinbefore, in basic medium,
then to the action of K2CO3, to yield a compound of formula (XIX): 
wherein R1, R2 and X are as defined hereinbefore,
which is subjected to the action of a reducing agent, such as LiAlH4 for example, to obtain a compound of formula (XVxe2x80x2), a particular case of the compounds of formula (XV): 
wherein R1, R2 and X are as defined hereinbefore,
wherein the compound of formula (XV) may be subjected to the conditions of oxidation to yield a compound of formula (XX), a particular case of the compounds of formula (II): 
wherein R1, R2 and X are as defined hereinbefore.
The compounds of the invention and the pharmaceutical compositions containing them prove to be useful in the treatment of disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact shown that they are atoxic, have a very high selective affinity for melatonin receptors and have substantial activities in respect of the central nervous system, and, in particular, therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties, as well as properties in respect of microcirculation have been found, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue caused by jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, that they have ovulation-inhibiting and immunomodulating properties and that they are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue caused by jet-lag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I), on its own or in combination with one or more pharmaceutically acceptable excipients.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral, nasal, percutaneous, transcutaneous, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragxc3xa9es, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and injectable or drinkable ampoules.
The dosage varies in accordance with the sex, age and weight of the patient, the administration route, the nature of the therapeutic indication, or possibly associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.
The following Examples illustrate the invention and do not limit it in any way. The following preparations yield synthesis intermediates useful in the preparation of the compounds of the invention.